Revolutionary and New Category in Skin Health 2019 Micah Chemistry - - PowerPoint PPT Presentation

Revolutionary and New Category in Skin Health

2019

Micah™ Chemistry

ante

ante- a prefix meaning “before,” of Latin origin

Micah anteoxidant™

Micah anteoxidantTM - to prevent the visible signs of photoaging,

• f Hallstar origin

Micah ante-oxidative stress

• inflammatory
• DNA damage
• pollution
• blue light
• UVA damage
• wrinkles
• collagen degradation
• fine lines
• aging

Micah anteoxidant™

CLINICALLY PROVEN TO Prevent 100% of UVA induced oxidative stress and DNA damage Prevent 55% of UVA induced inflammatory cytokines (IL-6) Prevent 35% of UVA induced matrix degrading enzymes (MMP-1) Prevent 31% of Visible Light induced oxidative stress

WORK IN CONCERT TO PROTECT CONSUMERS

HALLSTAR’S VISION: PROTECT CONSUMERS FROM THE ELEMENTS

UVB | UVA-II | UVA-I | VISIBLE LIGHT | IR | POLLUTION

CONSUMER CHOICES: EUROPE

CONSUMER CHOICES: EUROPE

5,413

Number of products launched with Anti-Pollution claims in EMEA since 2014

6,571

Number of products launched with UVA claims in EMEA since 2014

4x

Increase in products launched with Blue Light claims since 2016

THE MICAH COMPOUND & MECHANISM OF ACTION MICAH COMPOUND & SAFETY DOSSIER

Micah Compound:

n-Butyl Ester

▪ Fused Ring Cyanoacrylate ▪ Molecular Weight: 454 g/mol ▪ Proposed INCI: Polycyclic Di-Ester

(Official name expected Feb 2019)

▪ At projected Use Level in Cosmetic Lotion ≤ 0,75%:

► SPF negligible ► UVA absorbance negligible (~0.00001) ► No Visible Light absorption (at any use level)

▪ CAS:

Description

17

Micah: Compound

18 SAFETY DOSSIER Genotoxicity/Ames test ✓ Ocular irritation (HET-CAM) ✓ Phototoxicity Clinical – in vivo (22 volunteers) ✓ Phototoxicity 3D Skin Model – in vitro ✓ Phototoxicity Human Skin Explant - ex vivo ✓ Sensitization/HRIPT (50 volunteers) ✓

Micah Compound: Safety & Toxicology

THE MICAH COMPOUND & MECHANISM OF ACTION MECHANISM OF ACTION

UV & VISIBLE LIGHT: PENETRATION INTO HUMAN SKIN

PS

e.g. Porphyrins, Flavins

PS*

Photoexcited Chromophore

1 Endogenous photosensitizers (PS) absorb solar radiation – inducing of photoexcited states (PS*) 1

3O2

Molecular Oxygen

1O2

Singlet Oxygen

2

O2 .- H2O2

• OH

Excited photosensitizer (PS*) transfers energy to 3O2 to generate 1O2 and subsequent ROS / FR 2 3

▲ MMP-1, IL6, IL1a ▲Collagen I, III (V) Breakdown ▼Procollagen Production

VISIBLE SIGNS OF PHOTOAGING

MAPK Pathway ▲ AP-1 ▼TGF-b Oxidation ▲ 8-OH-dG ▲ DNA Damage ▲ Lipid Damage ▲ Protein Damage

ROS / FR can lead to DNA, lipid, protein damage and mediate production of MMPs, IL’s: PHOTOAGED SKIN 3

UVA / Vis

UVA / Visible Light-induced ROS/FR Generation: ‘Base Case’

PS

e.g. Porphyrins, Flavins

PS*

3O2

Molecular Oxygen

1O2

Singlet Oxygen

O2 .- H2O2

• OH

▲Collagen I, III (V) Breakdown ▼Procollagen Production

VISIBLE SIGNS OF PHOTOAGING

MAPK Pathway ▲ AP-1 ▼TGF-b Oxidation UVA / Vis

UVA / Visible Light-induced ROS/FR Generation: Sunscreens & Antioxidants

 SUNSCREENS: Specific sunscreens absorb and/or reflect UVA, but performance diminish in the UVA1

portion of the solar light spectrum. Sunscreens may ‘color’ in the near-Visible portion of the spectrum.

 SUNSCREENS  ANTIOXIDANTS

 ANTIOXIDANTS: Antioxidants seek to neutralize ROS / FR . . . but only after the ROS/FR cascade has started.

▲ MMP-1, IL6, IL1a ▲ 8-OH-dG ▲ DNA Damage ▲ Lipid Damage ▲ Protein Damage

PS

e.g. Porphyrins, Flavins

PS*

3O2

Molecular Oxygen

1O2

Singlet Oxygen

O2 .- H2O2

• OH

▲Collagen I, III (V) Breakdown ▼Procollagen Production

UV/Vis PHOTOAGING SURPRESSED

MAPK Pathway ▲AP-1 ▼TGF-b Oxidation UVA / Vis

UVA / Visible Light-induced ROS/FR Generation: Micah Chemistry

Micah Compound

▪ Micah quenches excited states of endogenous photosensitizers (PS*), suppressing the generation of singlet

• xygen (1O2) and subsequent ROS / FR.

▪ Micah stabilizes by an electron transfer mechanism, and therefore will not impart color onto skin.

▲ MMP-1, IL6, IL1a ▲ 8-OH-dG ▲ DNA Damage ▲ Lipid Damage ▲ Protein Damage

PS

e.g. Porphyrins, Flavins

PS*

3O2

Molecular Oxygen

O2 .- H2O2

• OH

▲Collagen I, III (V) Breakdown ▼Procollagen Production

UV/Vis PHOTOAGING SURPRESSED

MAPK Pathway ▲AP-1 ▼TGF-b Oxidation UVA / Vis

UVA / Visible Light-induced ROS/FR Generation: Micah Chemistry

Micah Compound ▲ MMP-1, IL6, IL1a ▲ 8-OH-dG ▲ DNA Damage ▲ Lipid Damage ▲ Protein Damage

1O2

Singlet Oxygen

“ It is of the highest importance to effectively fight Singlet Oxygen”

– Paolo Giacomoni, former R&D Director, Estee Lauder & L’Oreal

▪ Singlet Oxygen reacts with proteins, lipids and nucleic acids. ▪ Outside Cell: Lipid peroxidation ▪ Inside Cell: Pro-inflammatory cytokines and MMP-1

• ▼Skin elasticity
• ▼Skin resilience

▪ Damage to cell DNA; 8 OH-dG lesion

UVA / Visible Light-induced ROS/FR Generation: Singlet Oxygen 1O2

8 OH-dG

Micah suppresses the generation of Singlet Oxygen

• HaCaT cells pretreated with aminolevulinic acid (ALA), a strong photosensitizer of singlet oxygen - 1O2
• HaCaT cells fluoresce when irradiated at 630nm
• HaCaT cells pretreated with ALA and Micah show no fluorescence, indicating Micah quenched the electron

transfer cascade that produces singlet oxygen 1O2 and other ROS.

A B C Visible Light (-) Micah (-) Visible Light (+) Micah (-) Visible Light (+) Micah (+)

Cells pre-treated with ALA Cells pre-treated with ALA Cells pre-treated with ALA Protocol: The HaCat cells were seeded in the 60mm cell culture dishes, after the cells became confluent, the cells were treated with 8mM ALA for 2 hours, and then different concentration of Rx14401, from 0 (no Rx14401 control) to 2.0mM, were added to the cells. After 1 hour, each plate of cells was irradiated at 630 nm for 3 minutes (for no irradiation control, the wells are wrapped with aluminum foil). After washing with PBS buffer, the cells were stained with DFFDA for 30 minutes. The cells were washed with PBS 3 times again and lysated by sonication. The cell lysates were analyzed with fluorescent plate reader to access the cellular ROS.

Singlet Oxygen and ROS Prevention: in vitro

THE MICAH COMPOUND & MECHANISM OF ACTION

PROOF OF CONCEPT: ROS / FREE RADICAL PREVENTION – VISIBLE LIGHT ex vivo and in vivo Gematria Labs, Berlin, Germany

• Dr. Schrader Institute, Germany

Micah effectively prevented visible- light induced ROS / FR and

• utperformed 1% Vitamin E.

VISIBLE LIGHT CLINICAL STUDY: DESIGN

SUBJECTS ▪ 10 Subjects ▪ Skin Types I - III FORMULATIONS 1. Vehicle 2. Micah 0,2% 3. Micah 0,75% LIGHT SOURCE & RESPONSES ▪ Chemiluminescence – photon emission counts ▪ Visible Light: 400 – 700 nm

Day 1 Day 2 Day 3 Day 4

AM PM

2 ml / cm2 applied 2x per day (AM / PM) for 4 days Visible Light (400 – 700 nm)

Energy released from

• xidative stress in form of

photon. Photomultiplier tube (PMT) continuous monitoring and measurement of photon energy.

At a use level of 0,75%, Micah demonstrated a 31% reduction in visible light-induced oxidative

• stress. Further optimization possible with a higher does of Micah.

▼31%

VISIBLE LIGHT CLINICAL STUDY: RESULTS

No statistical difference

THE MICAH COMPOUND & MECHANISM OF ACTION

PROOF OF CONCEPT: UVA: IL6, 8-OHdG, MMP-1 in vivo / clinical studies on human patients Skin Investigation and Technology Hamburg, Germany

UVA CLINICAL STUDY: DESIGN

SUBJECTS ▪ 10 Subjects ▪ Skin Types I - III ▪ Age; 30.0 +/- 8.2 years FORMULATIONS 1. Untreated Skin 2. Untreated Skin / Irradiated 3. Micah 0,2% / Irradiated 4. Micah 0,5% / Irradiated RESPONSES ▪ DNA Damage (8-OH-dG) ▪ IL-6 (ELISA) ▪ MMP-1 (ELISA)

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14

AM PM

2 ml / cm2 applied 2x per day (AM / PM) for 14 days 20 J / cm2 UVA (320 – 400 nm)

t = 0 hrs and t = 24 hrs

UVA CLINICAL STUDY: DNA DAMAGE – 8-OH-dG

At use levels between 0,2 and 0,5%, Micah significantly reduced the presence of UVA-induced 8- OH-dG, a maker associated with photoaged skin. 8-OH-dG levels returned to baseline with Micah.

UVA CLINICAL STUDY: DNA DAMAGE – 8-OH-dG

High intensity

UVA CLINICAL STUDY: MMP-1

At a use level of 0,5%, Micah demonstrated a 35% reduction in the presence of MMP-1, a marker associated with the breakdown of the extracellular matrix. ▼35%

No statistical difference

UVA CLINICAL STUDY: IL-6

At a use level of 0,5%, Micah demonstrated a 55% reduction in the presence of IL-6, a marker associated with skin inflammation, redness, irritation and barrier function. ▼55%

THE MICAH COMPOUND & MECHANISM OF ACTION

PROOF OF CONCEPT: ROS / FREE RADICAL PREVENTION, IL1a, IL6, 8-OHdG, MMP-1 ex vivo human skin BEN GURION UNIVERSITY, ISRAEL

* Significantly different from non-irradiated controls # significantly different from irradiated vehicle

 Positive Controls →

* Significantly different from non-irradiated controls # significantly different from irradiated vehicle

 Positive Controls →

* Significantly different from non-irradiated controls # significantly different from irradiated vehicle

 Positive Controls →

* Significantly different from non-irradiated controls # significantly different from irradiated vehicle

 Positive Controls →

PROOF OF CONCEPT: EX VIVO HUMAN SKIN MMP-1

At a use level of 0.20%, Micah demonstrated the ability to prevent the formation of MMP-1, an enzyme associated with the breakdown of the extracellular matrix (n = 4).

* Significantly different from non-irradiated control # significantly different from irradiated control

Micah anteoxidant™

Micah anteoxidantTM - to prevent the visible signs of photoaging,

• f Hallstar origin

45

Thank you!

AGE REPAIR AGE PREVENTION

UVB UVA-II UVA-I VISIBLE IR HIGH ENERGY DEEPER SKN PENETRATION

ANTIOXIDANTS UV FILTERS

Micah effectively prevents ~100% of UVA-induced ROS and DNA damage and limits the overexpression of inflammatory cytokines (IL-6) and matrix degrading enzymes (MMP-1) By preventing light-induced oxidative stress, Micah can enable antioxidants to effectively scavenge ROS / free radicals from exogenous sources and other mechanisms.

Vehicle

VISIBLE LIGHT CLINICAL STUDY: FORMULATIONS

Micah at 0.75% Micah at 0.5%

UVA CLINICAL STUDY: FORMULATIONS

Vehicle Micah at 0.5% Micah at 0.2%